The evolution of strains of cells or organisms resistant to currently effective therapeutic agents is an ongoing medical problem. For example, the development of cancerous cells resistant to chemotherapeutic drugs has long been recognized as a problem in the oncology field. Once resistant cells develop, the therapeutic regime, in order to remain effective, must be modified to introduce other chemotherapeutic agents. Another example of this resistance problem is the development of strains of microbial, fungal, parasitic and viral pathogens resistant to one or more anti-infective agents. As a result, there is still a need for new anti-proliferative and anti-infective agents that are effective against strains of cells or organisms that have developed resistance to currently available agents.
In the field of anti-infective agents, a variety of different antibiotics have been developed and approved for use in humans over the years. An oxazolidinone ring containing antibiotic known as linezolid (see, compound 1), available under the trade name Zyvox®, has been approved for use as an anti-bacterial agent active against Gram-positive organisms. Unfortunately, linezolid resistant strains of organisms are already being reported (Tsiodras et al. (2001) LANCET 358: 207; Gonzales et al. (2001) LANCET 357: 1179; Zurenko et al. (1999) PROCEEDINGS OF THE 39TH ANNUAL INTERSCIENCE CONFERENCE ON ANTIBACTERIAL AGENTS AND CHEMOTHERAPY (ICAAC); San Francisco, Calif., USA, September 26-29).

Because linezolid is both a clinically effective and commercially significant anti-microbial agent, investigators have been working to develop other effective linezolid derivatives. Research has indicated that the oxazolidinone ring is important for linezolid activity. The literature commonly describes molecules having small groups substituted at the C-5 of the oxazolidinone ring, and early structure-activity relationships suggested that compounds with, larger groups at the C-5 position were less active as anti-bacterial agents. As a consequence, it is believed that, in general, investigators have been reluctant to place large substituents at the C-5 position of oxazolidinone rings in anti-microbial agents.
International patent publication no. WO 01/81350 discloses a series of C-5 substituted oxazolidinones (see, general structure 2) where the acetamido group of linezolid was replaced, for example, with an optionally substituted N-linked 5-membered heteroaryl ring or an N-linked 6-membered heteroaryl ring. The 5-membered heteroaryl ring may contain either (i) one to three further nitrogen heteroatoms, or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; wherein the ring is optionally substituted on a C-atom by an oxo or thioxo group; and/or is optionally substituted on a C-atom by one or two C1-4 alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternized) by C1-4 groups. The N-linked 6-membered heteroaryl ring may contain up to three nitrogen heteroatoms in total, wherein the ring is substituted on a suitable C-atom by oxo or thioxo groups, and optionally substituted on any available C-atom by one or two C1-4 alkyl groups.

In addition, International patent publication nos. WO 99/64416 and WO 00/21960 also disclose a series of 5-substituted oxazolidiniones (see, general structure 3). In particular, WO 99/64416 discloses compounds having the general structure 3, where X is —O— or —S— and HET is a C-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen atoms. WO 00/21960 discloses compounds having the general structure 3, where X is —N(H)— and HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S.

European Patent no. 0 097 469 B1 discloses intermediates of compound 4 which are useful in the synthesis of triazole anti-fungal agents of general structure 5. The intermediates may contain a disubstituted C-5 atom in the oxazolidinone ring, and the nitrogen atom of the oxazolidinone ring is a secondary amine.

Gregory and coworkers disclose the synthesis of a variety of oxazolidinone containing antibacterial agents (Gregory et al. (1989) J. MED. CHEM. 32: 1673-1681). Compound 6, a C-5 substituted five-membered heteroaryl derivative, was inactive as an antibacterial agent. This observation appears to be consistent with other oxazolidinone containing compounds that have the opposite stereochemical configuration at C-5 relative to that found in linezolid.

Oxazolidinone compounds similar to those of compound 8 have been formed via decomposition of substituted nitrosoureas 7 and have been useful as anticancer agents (Mulcahy et al. (1989) EUR J. CLIN. ONCOL. 5: 1099-1104; Carmiati et al. (1989) BIOCHEM. PHARMACOL. 38: 2253-2258).

U.S. Pat. No. 6,034,069 discloses a series of 3′-N-modified 6-O-substituted erythromycin ketolide derivatives similar to compound 9. The aryl group attached to the aminosaccharide moiety (represented by a 3-pyridyl group in 9) was variable, and non-aryl substituents were synthesized as well.

Published German patent application DE 196 04 223 A1 discloses oxazolidinone ring-containing compounds of the general structure 10, where R1 can be, in addition to other structures, a substituted or unsubstituted five-membered ring chosen from thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl and pyrrolidinyl.

U.S. Pat. No. 6,362,189 discloses antibiotic compounds having the general formula 11. To the extent that the chemical moiety denoted by the symbol “G” may be an oxazolidinone ring, the ring may be substituted with a thiocarbonyl functionality, namely a —CH2NHC(S)R1.

International patent publication no. WO 99/63937 proposes the synthesis of multivalent macrolide antibiotics comprising a portion of a macrolide antibiotic linked via a linker to a portion of another known antibacterial agent. Two of the compounds proposed, although apparently not made or tested, include those shown below having the formulas 13a and 13b.

Notwithstanding the foregoing, there is still an ongoing need for new anti-infective and anti-proliferative agents. There is also an ongoing need for new anti-inflammatory agents, and new agents to treat gastrointestinal motility disorders.